Reducing blood sugar with 3-alkyl-5-alkoxymethylisoxazole



United States Patent This invention relates to3-alkyl-5-alkoxymethylisoxazoles and to a method for their preparationand use.

The compounds of this invention are represented by the formulas F and R(Ell L,

wherein R and R are alkyl groups of 1-4 carbon atoms, n is an integerless than 3, and MS is a metal salt. These compounds have beenunexpectedly found to exhibit many times the oral hypoglycemic activityof tolbutamide in standard test animals, such as rats. The pronouncedactivity of these 3,5-disubstituted isoxazoles, coupled with their loworder of toxicity, makes pharmaceutical compositions containing thesecompounds useful in reducing the blood sugar content of mammals, and inparticular for administration by the preferred oral route.

Musante, Gazz. Chim. Ital. 68: 240 (1938), Chem. Centr., 193 8, II(1405), discloses the reaction of 4-imino- S-methoxy-Z-pentanone andhydroxylamine to give 5- methyl-3-methoxymethylisoxazole and observesexplicitly that the presently claimed 3-methyl-5-methoxymethylisoxazoleis not obtained because substitution of the imino group by the oximeradical occurs before ring formation. This reaction is as follows:

0133i lg-CHzOOH! (I) Musante also discloses the reaction ofethoxyacetylacetone with hydroxylamine as giving5-methyl-3-ethoxymethylisoxazole, as follows:

It has now been unexpectedly found, however, that the reaction of, forexample, methoxyacetylacetone with hydroxylamine gives the3-methyl-S-methoxymethylisoxazole (III) here claimed in isomeric mixturewith I above, according to the following:

CH O C 13 Patented Jan. 3, 1967 ICC a 1-a1koxy-4-alkylbutane-2,4-dione,in which the :alkyl groups contain 1-4 carbon atoms, and hydroxylamineto give an isomeric mixture of the corresponding 3-alkyl-5-alkoxymethylisoxazoles and 5-alkyl-3-alkoxymethylisoxazoles. Thismixture is then separated to give the desired3-a1kyl-S-alkoxymethylisoxazoles. The starting l-alkoxy-4-alkylbutane-2,4-diones, such as methoxyacetylacetone,ethoxyacetylacetone, isopropoxyacetylacetone andsec-butoxyacetylacetone, are prepared by known methods from theappropriate ethylalkoxyacetate and alkylmethylketone in the presence ofsodium ethoxide, according to the reaction:

in which R and R are alkyl groups containing 14 carbon atoms.

In utilizing the compositions and practicing the method of thisinvention, the exact schedule of administration in animals is determinedindividually according to the subjects age, weight, response to themedication and nature and severity of the condition being treated. Foruse in reducing the blood sugar content, for example, from about 25 toabout 500 mg. of 3,5-disubstituted isoxazole can be administered orallyas a single dose one to four times daily.

In addition to 3-alkyl-5-alkoxymethylisoxazoles as the sole activeingredient, other complementary ingredients can be included in thecomposition to secure advantageous combinations of properties especiallyadapted to individual situations in the treatment of the foregoingconditions. Thus, other hypoglycemic agents such as tolbutamide,chlorpropamide, phenformin hydrochloride, mesoxalic acid, insulin,nicotinic acid, and the like can be included in the present formulationsin amounts not exceeding and preferably less than those normallyemployed in single unit doses where such added ingredients are employedalone. Utilizable potassium salts, such as potassium chloride, can beincluded to offset possible potassium losses during therapy.

Such combinations include also conventional therapeutic amounts or lessof hypocholesteremic agents such as the D-isomer of3,S,3'-triiodothyronine, triiodothyropropionic acid, and thyroxine-likecompounds such as sodium L-thyroxine and sodium D-thyroxineglucocorticoids such as hydrocortisone, prednisolone and6a-methylprednisolone; anticoagulants such as heparin,2-diphenylacetyl-l,3-indandione, polyethylene sulfonate and dicumaml orits derivatives vitamins such as nicotinic acid, vitamin B ascorbic acidand pyridoxine hydrochloride; estrogens such as estradiol; androgenssuch as testosterone; combinations of estrogens and androgens such asestradiol and testosterone; unsaturated fatty acids or esters such aslinoleic acid or esters; antibiotics such as neomycin; analgesics suchas aspirin; compounds associated with cholesterol synthesis ormetabolism such as u-phenylbutyric acid and a-p-biphenylylbutyri-c acid;lipotrophic agents such as choline and inositol; amino acids such astaurine and glycine; sterols such as sitosterol and other plant sterols;diuretics such as ethoxaz-olamide and hydrochlorothiazide; anorexigenicagents such as amphetamine; cardiovascular agents (includingvasodilators and hypotensive agents), such as chlorisondamine chloride,hexamethonium chloride, and pentaerythritol tetranitrate.

In adapting the active ingredients for use in mammals, the novelcompositions are suitably presented for ad'- ministration in unit dosageform as tablets, pills, capsules,

. 3 powders, wafers, cachets, granules, oral aqueous or oil dispersions,including elixirs, and the like.

For preparing solid compositions such as tablets, the active ingredientis mixed with a conventional non-sugar tableting component such ascornstarch, dicalcium phosphate, terra alba (calcium sulfate), talc,stearic acid, calcium stearate, gums and functionally similar materialsconstituting pharmaceutical diluents or carriers. The tablets or pillscan be laminated or otherwise compounded to provide a dosage formaffording the advantage of prolonged or delayed action or ofpredetermined successive action of the enclosed medication. For example,the tablet or pill can comprise an inner dosage and outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of. polymeric acids or mixtures ofpolymeric acids with such materials as shellac, shellac and cetylalcohol, cellulose acetate phthalalte and the like. A

particularly advantageous sustained release coating comprises a styrenemaleic acid copolymer.

The liquid form in which the novel compositions of this invention can beincorporated include aqueous sugarfree solutions or suspensions,emulsions or suspensions with edible oils such as cottonseed oil, sesameoil, coconut oil, peanut oil and the like, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include the synthetic and natural gumssuch as tragacanth, acacia, dextran, methylcellulose,polyvinylpyrrolidone, gelatin and the like.

In preparing pharmaceutical compositions of 3-alkyl-5-alkoxymethylisoxazole, the fact that certain of these compounds arewater-insoluble, volatile liquids must be considered. Appropriate oralliquid dosage forms include conventional sugar-free syrups, elixirs andnon- 1aqueous solutions for use as drops or by the teaspoonful. Suitablenon-aqueous vehicles for oral use include the edible oils (e.g., peanutoil, cottonseed oil, coconut oil and other vegetable oils), mineral oil,glycerol, propylene glycol, polyethylene glycol 200-600, sorbitol,ethanol, or mixtures of these (e.g., equal parts of peanut oil andpropylene glycol). Aqueous vehicles include from about -1 to about 50%aqueous solutions of propylene glycol or ethanol or mixtures of the twocomprising together the said percentages. Liquid preparations forinstramuscular or subcutaneous injection can be prepared asethanolicaqueous, propylene glycol-aqueous or oil solutions (e.g.,vegetable oils such as peanut oil) and in repository-type vehicles suchas aluminum monostearate-peanut oil gel. In general, liquid formulationsrange in concentration from about 0.5 to 2040%3-alkyl-S-alkoxymethylisoxrazo e.

Solid dosage forms of liquid 3-alkyl-5-alkoxymethylisoxazole, such as3-methyl-5-methoxymethylisoxazole, require the intermediate preparationof the liquid active ingredient as discrete solid particles which can beempolyed to build the ultimate dosage form by conventional methods.Alternatively, the liquid 3-alkyl-5-alkoxymethylisoxazole can bedissolved or dispersed in an edible oil such as a vegetable or mineraloil (in ratios of, for example,' about 1:1 to 1:200) and soft elasticcapsules containingfthe oil dispersion or solution prepared for oraluse. Triturates of the present compounds can be made using variousabsorbing powders such as kaolin, magnesium carbonate, bentonite,magnesium oxide, starch, calcium carbonate, tribasic calcium phosphate,magnesium trisilicate and the like. Emulsifying the liquid activeingredient, preferably dissolved in a suitable .vegetable oil or mineraloil, to provide small particle sizes and then coating the said particleswith a coacervate of one or more hydrophilic colloids, pharmaceuticallyacceptable c-opolymers, or mixtures thereof yields, on drying,free-flowing granulations which can be handled essentially as solidparticles and formulated as powders, granules, tablets, hard-filledcapsules and .the like.

It has been found that a complex of a liquid 3-alkyl-5-alkoxymethylisoxazole with a pharmaceutically acceptable metal saltgives a crystalline solid which can be formulated on an equivalentweight basis into tablets, capsules, pills, powders, granules, pilules,and the like. Some metal salts are less desirable than others from thestandpoint of toxicity and hydroscopicity, and the zinc salts, such aszinc chloride, zinc bromide, zinc phosphate, zinc sulfate, zinc nitrate,zinc acetate, zinc carbonate, and the like, are preferred. However, thelike salts of other metals, such as iron, aluminum, magnesium andcalcium, can also be used.

In preparing the metal salt complexes of 3-alkyl-5-alkoxymethylisoxazole, such as 3 methyl 5 methoxymethylisoxazole,conventional procedures are employed to give complexes having either a1:1 or 2:1 ratio of isoxazole to metal salt. The 2:1 complex,bis-3-alky1-5- alkoxymethylisoxazole, is preferred because it provides ahigher proportion of isoxazole per unit weight of solid and is lesshygroscopic. Bringing together the desired metal salt and the desiredisoxazole in a common solvent, with stirring, is sufficient to producethe desired complex in high yield. A molar excess of isoxazole will givea 2:1 complex, less than a molar excess giving the 1:1 complex.

The term unit dosage form as used in the specification and claims hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in assocition with therequired pharmaceutical diluent, carrier or vehicle. The specificationfor the novel unit dosage forms of this invention are dictated by anddirectly dependent on (a) the unique characteristics of the activematerial and the particular therapeutic effect to be achieved and (b)the limitations inherent in the art of compounding such an activematerial for therapeutic use, as disclosed in detail in thisspecification, these being features of the present invention. Examplesof suitable unit dosage forms, as heretofore described, are tablets,capsules, pills, powder packets, wafers, cachets, granules, non-aqueoussolutions or suspensions for oral or sterile injectable use,suppositories, and segregated multiples of any of the foregoing, andother forms alluded to herein.

The following examples illustrate the best mode contemplated forcarrying out the invention, but such examples are not to be construed aslimiting the scope thereof.

Example 1.3-methyl-5-methoxymethylisoxazole A stirred mixture of 26.0gm. of methoxyacetylacetone, 20.8 gm. of hydroxylamine hydrochloride and20.8 gm. of potassium carbonate was heated over an oil bath at C. for 4hours. The mixture was allowed to cool and then was diluted with 75 ml.of water and extracted with ether. The ether extracts were dried overmagnesium sulfate and concentrated. The residue was distilled at reducedpressure through a 6-inch Vigreux column to give 15.36 gm. (60.5%) of acolorless liquid boiling at 7780 C. (12 mm.). Redistillation gave ananalytical sample boiling at 78 C. (12 mm.).

Analysis.Calculated for C H NO C, 56.68; H, 7.14; N, 11.02. Found: C,56.82; H, 7.42; N, 10.29.

The analytical sample above was further purified by vapor phasechromatography to give two distinct fractions. By nuclear magneticresonance one fraction was identified as3-methyl-S-methoxymethylisoxazole and the other as 5-methyl-3-methoxymethylisoxazole, each essentially free of the otherisomer.

Example 2 Following the procedure of Example 1 but substitutingequivalent amounts of other 1-alkoxy-4-alkylbutane- 2,4-diones for themethoxyacetylacetone therein, the alkyl groups containing 1-4 carbonatoms, gives the corresponding 3-alkyl-S-alkoxYmethylisoxazole, usuallyin isomeric mixture with the corresponding5-alkyl-3-alkoxymethylisoxazole, from which the desired 3-alkyl isomercan be separated. By this method there is prepared, for example, 3methyl 5 ethoxymethylisoxazole, 3 methyl 5- isopropoxymethylisoxazole, 3methyl 5 secbutoxymethylisoxazole, 3 ethyl 5 methoxymethylisoxazole, 3ethyl 5 ethoxymethylisoxazole, 3 ethyl 5 isopropoxymethylisoxazole, 3ethyl 5 sec butoxymethylisoxazole and the corresponding 3propyland3-sec-butyl derivatives of the foregoing compounds.

Example 3.Bis-3-methyl-5-m'eth0xymethylisoxaz0le zinc chloride complexExample 4 Substituting other 3 alkyl 5 alkoxymethylisoxazoles, such asthose of Example 2, for the S-methyl-S-methoxymethylisoxazole in theabove reaction gives the corresponding zinc chloride complexes thereof.

Example 5 In foregoing Examples 3 and 4, other pharmaceuticallyacceptable metal salts can be substituted for the zinc chloride, theamounts being determined on a molar equivalent basis. In particular,other zinc salts, such as zinc bromide, zinc phosphate, zinc sulfate,zine nitrate, zinc acetate, zinc carbonate and the like can be employed.

Example 6.- Sft gelatin capsules A batch of 1,000 soft gelatin capsules,each containing 25 mg. of 3-methyl-5methoxymethylisoxazole in mineraloil, is prepared from the following materials:

Gm. 3-methyl-S-methoxymethylisoxazole 25 Mineral oil, U.S.P. 100

A uniform dispersion of the active ingredient in the mineral oil isprepared and the dispersion filled into soft gelatin capsules byconventional means.

One capsule is given twice a day in the treatment of diabetes.

Example 7 .-N on-aqueous preparation One thousand milliliters of anon-aqueous liquid preparation containing 500 mg. of3-methyl-5-methoxymethylisoxazole in each teaspoonful ml.) is preparedby dispersing 100 gm. of active ingredient in a vehicle containing 600ml. of peanut oil and propylene glycol, q.s. to 1000 ml.

Example 8.Tablets A lot of 100,000 compressed tablets, each containing100 mg. of bis-3-methy1-5-methoxymethylsioxazole zinc chloride complex,is prepared from the following ingredients:

Bis-3 -methyl-5-methoxymethylisoxazole zinc chlor- Gm.

ide complex 10,000 Terra alba (calcium sulfate) 25,000 Methylcellulose,U.S.P. (15 cps.) 650 Talc, bolted 4,500 Calcium stearate, fine powder350 Example 9.Capsules A lot of 10,000 two-piece hard gelatin capsulesfor oral use, each containing 250 mg. ofbis-3-methyl-5-methoxymethylisoxazole zinc chloride complex, is preparedfrom the following materials: Bis-3-methyl-5-methoxymethylisoxaole zincchloride complex, 2500 gm.

The powdered bis-3-methyl-5-methoxymethylisoxazole zinc chloride complexis mixed with talc and starch and encapsulated in the usual manner.

One capsule is given once daily in the treatment of diabetes.

Example 10.Oil suspension An oil suspension for oral use, each 5 ml.containing 50 mg. of bis-3-methyl-S-methoxymethylisoxazole zinc chloridecomplex, is prepared from the following materials:

Saccharin sodium gm 0.5 Cyclamate sodium gm 0.1 Bis 3 methyl 5methoxymethylisoxazole zinc chloride complex gm Benzoic acid, powder gm0.5 Methylparaben gm 0.5 Butylated hydroxyanisole gm 0.05 Oil of orangeml 1 Aluminum monostearate-corn oil gel, q.s ml 10,000 One teaspoonful(5 mil.) is given twice daily in the treatment of diabetes.

Example 11 In each of foregoing Examples 6 through 10 the activeingredient can be replaced by other 3-alkyl-5-alkoxymethylisoxazoles andmetal complexes thereof, such as those identified in Examples 2 through5.

What is claimed is:

1. A therapeutic composition comprising: in dosage unit form, as theprimary active ingredient, from about 25 to about 500 mg. of a compoundselected from the group consisting of 3-methyl-5-methoxymethylisoxazoleand 3-methyl-5-methoxymethylisoxazole zinc chloride complex, incombination with a pharmaceutical carrier.

2. A method for reducing the blood sugar content of mammals comprising:administering to a mammal a 3-alkyl-5-alkoxymethylisoxazole selectedfrom the group consisting of compounds of the formula:

il-MS n and 7 wherein R and R are alkyl groups of 1-4 carbon atoms, n isan integer less than 3, and MS is a pharmaceutically acceptable metalsalt.

3. A method for reducing the blood sugar content of mammals comprising:administering to a mammal a compound selected from the group consistingof 3 methyl-5- methoxymethylisoxazole and3-methyl-5-methoxymethylisoxazole zinc chloride complex.

References Cited by the Examiner UNITED STATES PATENTS 2,260,256 10/1941Lippincott 260--307 8 Caspe 167-65 Gardner 260-307 Wright 167-65 Kano260--307 Heifer 260299 JULIAN S. LEVITT, Primary Examiner. FRANKCACCIAPAGLIA, m, s. ROSEN,

Examiners.

10 M. J. COHEN, J. D. GOLDBERG, Assistant Examiners.

3. A METHOD FOR REDUCING THE BLOOD SUGAR CONTENT OF MAMMALS COMPRISING:ADMINISTERING TO A MAMMAL A COMPOUND SELECTED FROM THE GROUP CONSISTINGOF 3-METHYL-5METHOXYMETHYLISOXAZOLE AND3-METHYL-5-METHOXYMETHYLISOXAZOLE ZINC CHLORIDE COMPLEX.